This project seeks to develop a novel gene transfer-based approach as an alternative to deep brain stimulation (DBS) in the treatment of advanced Parkinson's disease (PD). Viral gene transfer will be used to manipulate neuronal activity in basal ganglia structures. The underlying mechanism of DBS has not been clarified; the current hypotheses suggest either activation or inhibition of the brain regions targeted by high-frequency stimulation. The project employs an emerging technique to inhibit electrical activity in mammalian neurons by expressing a modified glutamate-gated chloride channel (GluCl) from C. elegans. Channel activation by ivermectin, an FDA-approved, a widely used anthelmintic, elicits a chloride conductance, clamping these neurons to the Nernst potential for chloride, thereby inhibiting action potentials ('silencing'). For this study the GluCl channel will be modified to convert it into a Na and K-selective, excitatory channel ("GluNa"). Adeno-associated and lentivirus vectors will be developed that encode both GluCl and GluNa. Thus, tools will be developed to stimulate or to inhibit neuronal activity. Injection of virus encoding either GluCl or GluNa channel into the subthalamic nucleus or substantia nigra pars reticulata will (1) provide a minimally invasive, adjustable approach to accomplish pharmacological DBS based on an FDA-approved drug, and (2) will generate further insights into the underlying mechanism of DBS. Aim 1 will provide a cation-selective channel. Aim 2 and 3 will test applicability of GluCl and GluNa (respectively) in the approach to pharmacological DBS. Both aims will give insights into the mechanism of DBS. to public health If successful, the project will establish a new treatment option for Parkinson's disease and could also be used in other applications where deep brain stimulation is now being tested. [unreadable] [unreadable] [unreadable]